Schizophrenia is a devastating psychiatric condition that affects approximately 0.4-1% of the US population. Substantial convergent evidence from drug studies, therapeutic treatments, and human imaging studies demonstrate that psychosis in schizophrenia is associated with a dysregulation of subcortical dopamine system function. This dopamine hypothesis of schizophrenia has one major caveat in that there appears to be no specific pathology in the midbrain dopamine system itself. Thus it is likely that it is the afferent regulation of the dopamine system that is dysfunctional in schizophrenia. Two such inputs are the medial prefrontal cortex (thought to be largely associated with cognitive deficits) and the hippocampus, a temporal lobe structure principally associated with learning and memory. Alterations in hippocampal structure and function in schizophrenia are consistently demonstrated in postmortem and neuro-imaging studies. Furthermore, there is increasing evidence for baseline hippocampal hyperactivity in human schizophrenia patients that is correlated with levels of psychosis. Consistent with this, we have recently reported baseline hyperactivity in the ventral hippocampus in a developmental disruption rodent model, namely MAM G17, that appears to be the driving force behind the dopamine hyperfunction in this model. Thus, attenuation of ventral hippocampal output may act to normalize dopamine transmission and may provide a novel therapeutic target. We plan to examine this model utilizing distinct approaches aimed specifically at modulating ventral hippocampal activity along the following Specific Aims: 1) Examine potential novel methods for regulating vHipp function in MAM and saline rats, 2) Determine how these methods for attenuating vHipp activity alter dopamine system function in MAM and saline rats, and 3) Determine whether attenuating vHipp system function can reverse behavioral deficits associated with schizophrenia in the MAM model. Examining the functional interactions among these systems and how disruption within this circuit affects information processing, neurochemistry and behavior is central to our ultimate goal of identifying new and improved therapeutic agents.

Public Health Relevance

Schizophrenia is a devastating psychiatric condition that affects 0.4% of the US population. One brain region commonly associated with this disease is the hippocampus. In this project we will examine novel methods for altering activity in this brain region in an attempt to better understand disease pathophysiology, with the ultimate goal being the development of improved therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH090067-05
Application #
8685327
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Neary, Jennifer L; Perez, Stephanie M; Peterson, Kara et al. (2017) Comparative analysis of MBD-seq and MeDIP-seq and estimation of gene expression changes in a rodent model of schizophrenia. Genomics 109:204-213
Carreno, Flavia R; Collins, Gregory T; Frazer, Alan et al. (2017) Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects. Int J Neuropsychopharmacol 20:504-509
Donegan, J J; Tyson, J A; Branch, S Y et al. (2017) Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. Mol Psychiatry 22:1492-1501
Donegan, Jennifer J; Lodge, Daniel J (2017) Cell-based therapies for the treatment of schizophrenia. Brain Res 1655:262-269
Carreno, F R; Donegan, J J; Boley, A M et al. (2016) Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry 21:1298-308
Perez, Stephanie M; Aguilar, David D; Neary, Jennifer L et al. (2016) Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia. Neuropsychopharmacology 41:477-86
Donegan, Jennifer J; Lodge, Daniel J (2016) Hippocampal Perineuronal Nets Are Required for the Sustained Antidepressant Effect of Ketamine. Int J Neuropsychopharmacol :
Jett, Julianne D; Boley, Angela M; Girotti, Milena et al. (2015) Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology (Berl) 232:3123-33
Cardenas, Damon P; Muir, Eric R; Huang, Shiliang et al. (2015) Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals. Neuroimage 119:382-9
Perez, Stephanie M; Chen, Li; Lodge, Daniel J (2014) Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia. Psychoneuroendocrinology 47:88-97

Showing the most recent 10 out of 22 publications